Objective: To clarify in patients with covid-19 the recovery rate of smell and taste, proportion with persistent dysfunction of smell and taste, and prognostic factors associated with recovery of smell and taste. Design: Systematic review and meta-analysis. Data sources: PubMed, Embase, Scopus, Cochrane Library, and medRxiv from inception to 3 October 2021. Review methods: Two blinded reviewers selected observational studies of adults (≥18 years) with covid-19 related dysfunction of smell or taste. Descriptive prognosis studies with time-to-event curves and prognostic association studies of any prognostic factor were included. Data extraction and synthesis: Two reviewers extracted data, evaluated study bias using QUIPS, and appraised evidence quality using GRADE, following PRISMA and MOOSE reporting guidelines. Using iterative numerical algorithms, time-to-event individual patient data (IPD) were reconstructed and pooled to retrieve distribution-free summary survival curves, with recovery rates reported at 30 day intervals for participants who remained alive. To estimate the proportion with persistent smell and taste dysfunction, cure fractions from Weibull non-mixture cure models of plateaued survival curves were logit transformed and pooled in a two stage meta-analysis. Conventional aggregate data meta-analysis was performed to explore unadjusted associations of prognostic factors with recovery. Main outcome measures: The primary outcomes were the proportions of patients remaining with smell or taste dysfunction. Secondary outcomes were the odds ratios of prognostic variables associated with recovery of smell and taste. Results: 18 studies (3699 patients) from 4180 records were included in reconstructed IPD meta-analyses. Risk of bias was low to moderate; conclusions remained unaltered after exclusion of four high risk studies. Evidence quality was moderate to high. Based on parametric cure modelling, persistent self-reported smell and taste dysfunction could develop in an estimated 5.6% (95% confidence interval 2.7% to 11.0%, I ² =70%, τ ² =0.756, 95% prediction interval 0.7% to 33.5%) and 4.4% (1.2% to 14.6%, I ² =67%, τ ² =0.684, 95% prediction interval 0.0% to 49.0%) of patients, respectively. Sensitivity analyses suggest these could be underestimates. At 30, 60, 90, and 180 days, respectively, 74.1% (95% confidence interval 64.0% to 81.3%), 85.8% (77.6% to 90.9%), 90.0% (83.3% to 94.0%), and 95.7% (89.5% to 98.3%) of patients recovered their sense of smell (I ² =0.0-77.2%, τ ² =0.006-0.050) and 78.8% (70.5% to 84.7%), 87.7% (82.0% to 91.6%), 90.3% (83.5% to 94.3%), and 98.0% (92.2% to 95.5%) recovered their sense of taste (range of I ² =0.0-72.1%, τ ² =0.000-0.015). Women were less likely to recover their sense of smell (odds ratio 0.52, 95% confidence interval 0.37 to 0.72, seven studies, I ² =20%, τ ² =0.0224) and taste (0.31, 0.13 to 0.72, seven studies, I ² =78%, τ ² =0.5121) than men, and patients with greater initial severity of dysfunction (0.48, 0.31 to 0.73, five studies, I ² =10%, τ ² <0.001) or nasal congestion (0.42, 0.18 to 0.97, three studies, I ² =0%, τ ² <0.001) were less likely to recover their sense of smell. Conclusions: A substantial proportion of patients with covid-19 might develop long lasting change in their sense of smell or taste. This could contribute to the growing burden of long covid. Systematic review registration: PROSPERO CRD42021283922.

PURPOSE: The US Food and Drug Administration has granted regulatory approval for the use of nivolumab—an immune checkpoint inhibitor (ICI)—in the first-line treatment of advanced gastric or esophageal adenocarcinoma (GEAC), regardless of programmed death-ligand 1 (PD-L1) expression. However, the efficacy of ICIs in low PD-L1–expressing tumors remains unclear.MATERIALS AND METHODS: This study aims to reconstruct unreported Kaplan-Meier (KM) plots of PD-L1 combined positive score (CPS) subgroups of randomized phase III trials comparing the addition of ICIs with conventional chemotherapy in the first-line treatment of GEAC. A graphical reconstructive algorithm was adopted to estimate time-to-event outcomes from reported overall survival and progression-free survival (OS and PFS) KM plots describing overall or subgroup cohorts. Using reconstructed time-to-event outcomes, KMSubtraction conducts bipartite matching of patients from the reported subgroup among the overall cohort. By excluding matched patients, KM plots and survival analyses of the unreported subgroups were retrieved.RESULTS: CheckMate-649, KEYNOTE-062, and KEYNOTE-590 were included. Two PD-L1 subgroups were identified with data unreported in the primary manuscripts: PD-L1 CPS 1-4 from CheckMate-649 and PD-L1 CPS 1-9 from KEYNOTE-062. No significant differences in OS and PFS were demonstrated in ICI-chemotherapy combinations when compared with chemotherapy among CheckMate-649 PD-L1 CPS 1-4 (OS: hazard ratio [HR] = 0.950, 95% CI, 0.747 to 1.209, P = .678; PFS: HR = 0.958, 95% CI, 0.743 to 1.236, P = .743) and KEYNOTE-062 PD-L1 CPS 1-9 subgroups. In the KEYNOTE-062 PD-L1 CPS 1-9 subgroup, patients treated with pembrolizumab had an increased hazard of tumor progression (HR = 2.092, 95% CI, 1.661 to 2.635, P < .001).CONCLUSION: Using KMSubtraction, data of PD-L1 subgroups previously unreported by primary manuscripts of pivotal clinical trials were retrieved. These data suggest the lack of benefit in the addition of ICI to chemotherapy in low PD-L1–expressing GEAC tumors.

The exact role of laparoscopic liver resection (LLR) in patients with hepatocellular carcinoma (HCC) and underlying liver cirrhosis (LC) is not well defined. In this meta-analysis, both long- and short-term outcomes following LLR versus open liver resection (OLR) were analysed. PubMed, EMBASE, Scopus and Web of Science databases were searched systematically for randomised controlled trials (RCTs) and propensity-score matched (PSM) studies reporting outcomes of LLR versus OLR of HCC in patients with cirrhosis. Primary outcome was overall survival (OS). This was analysed using one-stage (individual participant data meta-analysis) and two-stage (aggregate data meta-analysis) approaches. Secondary outcomes were operation duration, blood loss, blood transfusion, Pringle manoeuvre utilization, overall and major complications, length of hospital stay (LOHS), 90-day mortality and R0 resection rates. Eleven studies comprising 1618 patients (690 LLR versus 928 OLR) were included for analysis. In the one-stage meta-analysis, an approximately 18.7 per cent lower hazard rate (HR) of death in the LLR group (random effects: HR 0.81, 95 per cent confidence interval [C.I.] 0.68 to 0.96; P = 0.018) was observed. Two-stage meta-analysis resulted in a pooled HR of 0.84 (95 per cent C.I. 0.74 to 0.96; P = 0.01) in the overall LLR cohort. This indicated a 16–26 per cent reduction in the HR of death for patients with HCC and cirrhosis who underwent LLR. For secondary outcomes, LLR was associated with less blood loss (mean difference [MD] −99 ml, 95 per cent C.I. −182 to −16 ml), reduced overall complications (odds ratio 0.49, 95 per cent C.I. 0.37 to 0.66) and major complications (odds ratio 0.45, 95 per cent C.I. 0.26 to 0.79), and shorter LOHS (MD −3.22 days, 95 per cent C.I. −4.38 to −2.06 days). Laparoscopic resection of HCC in patients with cirrhosis is associated with improved survival and perioperative outcomes.

Gastric cancer is a major cause of global cancer mortality. To explore geospatial interactions in gastric tumors, we integrated 2,138 spatial transcriptomic regions of interest with 152,423 single-cell expression profiles across 226 cancer samples from 121 patients. We observed pervasive expression-based intratumor heterogeneity, recapitulating tumor progression through spatially localized and functionally ordered subgroups associated with specific immune microenvironments, checkpoint profiles, and genetic drivers (SOX9). Phylogenetic analysis revealed two separate evolutionary trajectories (branched evolution and internal diaspora evolution) associated with distinct molecular subtypes, clinical prognoses, and stromal neighborhoods, including VWF+ ACKR1+ endothelial cells. Spatial analysis of tumor–stroma interfaces across multiple gastric cancers highlighted new ecosystem states not attributable to mere tumor/stroma admixture, landmarked by increased GREM1 expression. Our results provide insights into how the cellular ecosystems of individual gastric cancers are sculpted by tumor-intrinsic and extrinsic selective pressures, culminating in individualized patient-specific cancer cartographies. Significance: Integration of spatial transcriptomic (GeoMx Digital Spatial Profiler) and single-cell RNA sequencing data from multiple gastric cancers identifies spatially resolved expression-based intratumoral heterogeneity, associated with distinct immune microenvironments. We uncovered two separate evolutionary trajectories associated with specific molecular subtypes, clinical prognoses, stromal neighborhoods, and genetic drivers. Tumor–stroma interfaces emerged as a unique state of tumor ecology.

Background: Data from certain subgroups of clinical interest may not be presented in primary manuscripts or conference abstract presentations. In an effort to enable secondary data analyses, we propose a workflow to retrieve unreported subgroup survival data from published Kaplan-Meier (KM) plots. Methods: We developed KMSubtraction, an R-package that retrieves patients from unreported subgroups by matching participants on KM plots of the overall cohort to participants on KM plots of a known subgroup with follow-up time. By excluding matched patients, the opposing unreported subgroup may be retrieved. Reproducibility and limits of error of the KMSubtraction workflow were assessed by comparing unmatched patients against the original survival data of subgroups from published datasets and simulations. Monte Carlo simulations were utilized to evaluate the limits of error of KMSubtraction. Results: The validation exercise found no material systematic error and demonstrates the robustness of KMSubtraction in deriving unreported subgroup survival data. Limits of error were small and negligible on marginal Cox proportional hazard models comparing reconstructed and original survival data of unreported subgroups. Extensive Monte Carlo simulations demonstrate that datasets with high reported subgroup proportion (r = 0.467, p < 0.001), small dataset size (r = − 0.374, p < 0.001) and high proportion of missing data in the unreported subgroup (r = 0.553, p < 0.001) were associated with uncertainty are likely to yield high limits of error with KMSubtraction. Conclusion: KMSubtraction demonstrates robustness in deriving survival data from unreported subgroups. The limits of error of KMSubtraction derived from converged Monte Carlo simulations may guide the interpretation of reconstructed survival data of unreported subgroups.